title: Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting.
abstract: Vascular networks develop from a growing vascular front that responds to VEGF and other guidance cues. Angiogenesis is required for normal tissue function, but, under conditions of stress, inappropriate vascularization can lead to disease. Therefore, inhibition of angiogenic sprouting may prevent neovascularization in patients with blinding neovascular eye diseases, including macular degeneration. VEGF antagonists have therapeutic benefits but also can elicit off-target effects. Here, we found that the Ras pathway, which functions downstream of a wide range of cytokines including VEGF, is active in the growing vascular front of developing and pathological vascular networks. The endogenous Ras inhibitor p120RasGAP was expressed predominately in quiescent VEGF-insensitive endothelial cells and was ectopically downregulated in multiple neovascular models. MicroRNA-132 negatively regulated p120RasGAP expression. Experimental delivery of α-miR-132 to developing mouse eyes disrupted tip cell Ras activity and prevented angiogenic sprouting. This strategy prevented ocular neovascularization in multiple rodent models even more potently than the VEGF antagonist, VEGF-trap. Targeting microRNA-132 as a therapeutic strategy may prove useful for treating multiple neovascular diseases of the eye and for preventing vision loss regardless of the neovascular stimulus.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Westenskow
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Scheppke
authors.forename: Stacey K
authors.initials: SK
authors.lastname: Moreno
authors.forename: Carli
authors.initials: C
authors.lastname: Wittgrove
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchetti
authors.forename: Iacovos P
authors.initials: IP
authors.lastname: Michael
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Anand
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: David
authors.initials: D
authors.lastname: Cheresh
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020729:p120 GTPase Activating Protein / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D011973:Receptors, LDL; C036053:VLDL receptor; D042461:Vascular Endothelial Growth Factor A; D020729:p120 GTPase Activating Protein; C467480:vascular endothelial growth factor A, mouse; D018631:ras Proteins